Reactive oxygen species (ROS) play an important role in the development of neurovascular diseases, including stroke, dementia, multiple sclerosis, and Parkinson's disease. This is due, in large part, to excess production of oxidants, decreased nitric oxide (NO) bioavailability, and decreased antioxidant capacity in the vasculature of the central nervous system.1-4 
A major source for vascular ROS is a family of nonphagocytic NAD(P)H (nicotinamide adenine dinucleotide phosphate) oxidases, including the prototypic Nox2 homolog-based NAD(P)H oxidase.5 NAD(P)H oxidase-derived ROS plays a physiological role in the regulation of endothelial function and vascular tone and a pathophysiological role in multiple processes, including endothelial dysfunction, inflammation, hypertrophy, and apoptosis which could affect cardiovascular and neurovascular remodeling.5 These findings have evoked considerable interest because of the possibilities that therapies against nonphagocytic NAD(P)H oxidase may decrease ROS generation. Additionally, strategies to increase nitric oxide (NO) availability and antioxidants may be useful in minimizing vascular injury and inflammation and thereby prevent or regress target organ damage associated with cognitive dementia, including hypertension, dyslipidemia, and diabetes.
The enzyme NADPH oxidase is a membrane-bound enzyme complex. It can be found in the plasma and phagosome membranes.7 NADPH oxidase is made up of five phagocytic oxidase subunits (“phox”, including p22, p40, p47, p67, and p90 phox) and a Rho guanosine triphosphatase.8 Under normal circumstances, NADPH oxidase is latent in neutrophils and enzymatic activation occurs to assemble in the membranes during respiratory burst. The enzyme generates superoxide by transferring electrons from NADPH inside the cell across the membrane and coupling these to molecular oxygen to produce the superoxide, which is a reactive free-radical.5 Superoxide can be produced in phagosomes, which contain ingested bacteria and fungi, or it can be produced outside of the cell. In a phagosome, superoxide can spontaneously form hydrogen peroxide that will undergo further reactions to generate reactive oxygen species (ROS).
As noted above, NADPH oxidase is associated with vascular and inflammatory diseases, and NADPH oxidase inhibitors may reverse these processes.9 NADPH oxidase produces ROSs, and these molecules activate an enzyme that makes the macrophages adhere to the artery wall (by polymerizing actin fibers). This process is counterbalanced by NADPH oxidase inhibitors and by antioxidants.10-12 For example, NADPH oxidase can be inhibited by apocynin and diphenyleneiodonium (DPI) by preventing the assembly of its subunits.13 In vitro studies have found that apocynin and DPI depolymerize the actin, break the adhesions, and allow foam cells to migrate out of the intima.14, 15 
There is considerable interest in the antioxidative and antiinflammatory effects of phenolic compounds from different botanical sources.16, 17 Oxidative mechanisms are associated with central nervous system disorders such as stroke and dementia. The evaluation of neuroprotective effects of phenolic compounds are gaining considerable interest as therapeutic agents.18-20 Some examples include resveratrol from grape and red wine, curcumin from turmeric, apocynin from Picrorrhiza kurroa, and epi-gallocatechin from green tea.21, 22 Increased production of reactive oxygen species (ROS) has been implicated in various chronic diseases, including neurodegenerative diseases.23 Oxidative stress is implicated in endothelial dysfunction, inflammation, hypertrophy, apoptosis, fibrosis, angiogenesis, and rarefaction.24 
Apocynin (4-hydroxy-3-methoxyacetophenone) is a major active ingredient from the rhizomes of Picorrhiza kurroa, a botanical plant used as an herbal medicine for potential treatment of a number of inflammatory diseases. Recently, apocynin is regarded as a specific inhibitor for NADPH oxidase in cell and animal models. In vitro studies indicate conversion of apocynin to diapocynin in the presence of peroxidases, e.g., myeloperoxidase, posing the possibility that diapocynin also contributes to the anti-oxidative action of apocynin.45 
Alpha lipoic acid (LA) is a naturally occurring eight-carbon fatty acid that is synthesized by plants and animals, including humans. The natural configuration is “R”, although the RS (DL) lipoic acid is extensively used commercially.26 It is chemically named 1,2-dithiolane-2-pentanoic acid (also referred to as thioctic acid). It is an important cofactor in the mitochondrial respiratory chain and serves as a cofactor for many enzyme reactions.27-29 It has also emerged as a potent antioxidant, antiinflammatory, and a mitochondrial protective agent.30 Both the parent compounds as well as the dihydro form (both the sulfur atoms reduced to thiol functions) have been reported to have antioxidant properties.26 LA has been reported to lower serum triglycerides, increase glucose uptake by cells, stimulate neurological function, decrease liver toxicity, increase levels of glutathione and ascorbic acid and decrease the expression of inflammatory molecules.31-34 LA has also been shown to have a neuroprotective effect.43, 44 LA has a very short half-life in the bloodstream as it undergoes rapid metabolism in the liver.72 Dosing 3-4 times daily is necessary to accomplish reasonable blood levels. This rather limited bioavailability of LA could be extended by suitably incorporating chemical groups to attenuate the metabolic process in the liver.35, 36 
It was recently demonstrated in humans that the combination of LA with the angiotensin receptor blocker irbesartan markedly reduced pro-inflammatory soluble IL-6 and VCAM-1 levels and improved vascular endothelial function.37 Covalent linkage of LA with ibuprofen has been demonstrated to be neuroprotective in rodent models of Alzheimer's disease in which administration of the co-drug decreased the oxidative damage due to the infusion of Aβ (1-40).48 In addition, a co-drug produced by chemically linking LA with L-Dopa, or dopamine, decreased neuronal oxidative damage associated with the administration of L-Dopa or dopamine alone.49 